Understanding normal and abnormal brain development requires knowledge of the cellular events whereby differential experience influences the ontogeny of neural structure and function. Research in this area of auditory neuroscience has achieved a new level of clinical importance through universal newborn screening and enormously increased use of cochlear implants in congenitally and prelingually hearing impaired infants. This application seeks continued funding for a research program aimed at understanding the cellular events whereby the integrity and bioelectric activity of the inner influences development of brainstem auditory pathways. Two separate lines of investigation are proposed. 1. We will continue investigating the intercellular and intracellular signaling pathway(s) that underlie a critical period for susceptibility to neuronal death following the elimination of excitatory synaptic input to the mammalian cochlear nucleus. We propose a series of experiments to further examine developmental changes in transcription and protein expression in the murine cochlear nucleus over the period of hearing development. This pattern will be compared with data from similar analyses of cochlear nucleus tissue from several mutant mouse models of early onset inner ear structural and functional pathologies causing deafness. These studies will provide a library of biomarker profiles for better understanding of normal and hearing deprived cochlear nucleus development that can be used to assess disease states and attempts at remediation. 2. We combine single cell labeling, electrophysiology, calcium imaging and dynamic structural imaging methods to study the cellular pathways underlying afferent regulation of dendritic structure. We also test the hypothesis that a protein responsible for transporting intracellular calcium to the extracellular environment, PMCA2, is essential for maintenance of normal dendritic stability. These studies make use of the unique spatially segregated binaural innervation of n. laminaris cells to allow spatial resolution of the relationships between afferent stimulation, calcium homeostasis, calcium regulatory proteins and structural dynamics of dendrites.